張雪微， 王 鵬， 宋 妮， 張秀麗， 王 聰， 李 明

(中國海洋大學(xué)醫(yī)藥學(xué)院海洋藥物教育部重點(diǎn)實(shí)驗(yàn)室，山東 青島 266003)

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11-deoxyheloside A的合成*

張雪微， 王 鵬， 宋 妮， 張秀麗， 王 聰， 李 明**

(中國海洋大學(xué)醫(yī)藥學(xué)院海洋藥物教育部重點(diǎn)實(shí)驗(yàn)室，山東 青島 266003)

首次完成天然膽甾烷型皂苷11-deoxyheloside A的合成。在相轉(zhuǎn)移催化的條件下，葡萄糖溴苷1與膦酸單乙酯2反應(yīng)以69%的收率得到葡萄糖膦酸酯供體3；以膽甾烷苷元4為原料，經(jīng)Luche還原和乙?；磻?yīng)以及三氟甲磺酸負(fù)載硅膠脫除TBDPS基團(tuán)得到膽甾烷二醇10；在金催化劑的作用下，膽甾二醇10與葡萄糖膦酸酯供體3進(jìn)行糖苷化反應(yīng)，然后脫除酰基保護(hù)基以97%的產(chǎn)率完成11-deoxyheloside A的合成。

11-deoxyheloside A；葡萄糖膦酸酯；金催化糖苷化

皂苷是一類具有多種藥效活性的糖綴合物，廣泛存在于傳統(tǒng)藥用植物中，具有抗腫瘤、抗病毒、抗菌、抗炎、抗寄生蟲、免疫調(diào)節(jié)等多種生物活性[1]。黃地百合(Chamaeliriumluteum(L.) A. Gray)的根和莖是傳統(tǒng)的中藥材，用于治療女性生殖系統(tǒng)疾病[2]。至2012年，已從黃地百合中分離得到一系列開鏈甾體皂苷[2](見圖1)，但由于它們的含量低微以及分離提取困難，限制了其構(gòu)效關(guān)系和深入的藥理活性研究。11-deoxyheloside A(見圖1)作為黃地百合膽甾烷皂苷的代表，至今未見對其的化學(xué)合成報(bào)道。本文以易得的膽甾烷苷元4和葡萄糖溴苷1為原料，采用金催化的鄰炔基膦酸酯糖苷化方法完成了11-deoxyheloside A的全合成，為合成黃地百合中系列膽甾烷型皂苷奠定了基礎(chǔ)。

圖1 11-deoxyheloside A和相關(guān)皂苷的結(jié)構(gòu)

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

試劑 TBDPSCl(叔丁基二苯基氯硅烷)，NaBH4，DIPEA(二異丙基乙基胺)等均為阿拉丁試劑公司產(chǎn)品，直接用于反應(yīng)。膽甾烷苷元4為實(shí)驗(yàn)室已有原料。未經(jīng)特殊說明，其余所用的試劑為國產(chǎn)分析純。1,2-二氯乙烷、CH2Cl2經(jīng)過CaH2回流重蒸處理，所用石油醚為60～90℃沸程。硅膠柱層析所用硅膠購自青島海洋化工廠分廠，規(guī)格為300～400目。

儀器 JEOLJNM-ECP 600 MHz和Bruker ARX500 (500 MHz)核磁共振波譜儀; JASCO P-1020自動(dòng)比旋光儀; 85-2型恒溫磁力攪拌器; 旋轉(zhuǎn)蒸發(fā)儀(BUCHI, R-114:EYELA, DTC- 21)。

1.2 實(shí)驗(yàn)操作

1.2.1 化合物3的合成 膦酸單乙酯2 (0.162 g, 0.61 mmol)溶于CHCl3(40 mL)中，加入K2CO3(0.169 g, 1.22 mmol), 甲基三辛基氯化銨(0.296 g, 0.732 mmol)和H2O (40 mL), 40 ℃下劇烈攪拌，分3次加入葡萄糖溴苷1(0.6 g, 0.93 mmol)，TLC檢測反應(yīng)完全。分出有機(jī)相，加入CHCl3稀釋。依次用飽和NaHCO3水溶液, 5% Na2S2O3水溶液和飽和食鹽水洗滌，無水Na2SO4干燥。抽濾、濃縮后硅膠柱層析純化(Petroleum ether:EtOAc=4:1-2:1)得到淡黃色泡沫狀固體3 (356 mg, 0.42 mmol, 69%); Rf0.10 (Petroleum ether:EtOAc=2:1):1H NMR (600 MHz, CDCl3)δ8.07 (dd,J=8.4,1.3 Hz, 2H), 8.01-7.99 (m, 3H), 7.95-7.87 (m, 11H), 7.84-7.79 (m, 6H), 7.68-7.65 (m, 2H), 7.58-7.25 (m, 41H), 7.22 (dd,J=8.3, 7.5 Hz, 2H), 7.11-7.04 (m, 4H), 6.92-6.88 (m, 1H), 5.92-5.82 (m, 6H),5.78-5.63 (m, 6H), 4.70 (dd,J=12.2, 2.9 Hz, 1H), 4.52 (dd,J=12.2, 5.1 Hz, 1H), 4.41 (dd,J=12.1, 3.0 Hz, 2H), 4.37-4.33 (m, 1H), 4.30 (dd,J=12.1, 5.2 Hz, 2H), 4.20-4.16 (m, 4H), 3.97-3.90 (m, 2H), 3.88-3.80 (m, 2H),2.49-2.43 (m, 6H), 1.64-1.59 (m, 6H), 1.52-1.46 (m, 6H), 1.27 (t,J=7.1 Hz, 3H), 1.01-0.93 (m, 15H);13C-NMR (150 MHz, CDCl3)δ165.9, 165.8, 165.6, 165.1, 165.0, 164.9, 164.7, 133.45, 133.40, 133.36, 133.27, 133.22, 133.18, 133.12, 133.0, 132.9, 132.77, 132.72, 131.9, 131.8, 129.81, 129.78, 129.72, 129.71, 129.6, 129.48, 129.43, 128.9, 128.7, 128.6, 128.5, 128.38, 128.36, 128.24, 128.22, 128.0, 126.9, 126.8, 126.7, 126.64,126.60,126.4,126.3,96.9,96.8,95.7 (d,J=4.7 Hz), 95.2 (d,J=5.8 Hz), 78.6 (d,J=6.3 Hz), 78.4 (d,J=6.7 Hz), 72.9, 72.8, 72.70, 72.68, 71.8 (d,J=7.9 Hz), 71.5 (d,J=8.4 Hz), 69.2, 69.1, 62.64, 62.56, 62.5 (d,J=1.7 Hz), 62.3 (d,J=7.0 Hz), 30.5, 30.4, 22.0, 21,9, 19.4, 19.3, 16.0, 15.9 (d,J=7.2 Hz), 15.8 (d,J=6.7 Hz), 13.7, 13.6;31P NMR (243 MHz, CDCl3)δ18.29, 17.90; ESI-HRMS calcd for C48H46O12P[M+H]+845.2721, Found 845.2705。

1.2.2 化合物5的合成 化合物4 (0.6 g, 0.79 mmol)溶于MeOH和CH2Cl2(11 mL，v:v=9:2)的混合溶劑中，加入MeONa (8.6 mg, 0.16 mmol)，室溫反應(yīng)過夜，TLC顯示反應(yīng)完全。Dowex-50(H+)樹脂調(diào)pH至中性。過濾、濃縮，硅膠柱層析純化(Petroleum ether:AcOEt=2.5:1)得到白色泡沫狀固體5 (0.49 g, 0.69 mmol, 87%)：1H NMR (500 MHz, CDCl3)δ7.70-7.64 (m, 4H), 7.43-7.33 (m, 6H), 5.10 (d,J=5.2 Hz, 1H), 4.95 (td,J=8.0, 4.9 Hz, 1H), 3.56-3.48 (m, 1H), 3.41 (d,J=5.8 Hz, 1H), 2.97-2.91 (m, 1H), 2.65-2.58 (m, 1H), 2.43-2.26 (m, 1H), 2.15-2.09 (m, 1H), 1.95 (s, 3H), 1.92-1.80 (m, 4H), 1.76-1.64 (m, 5H), 1.63-1.15 (m, 9H), 1.12 (d,J=7.1 Hz, 3H), 1.05 (s, 9H), 0.98 (s, 3H), 0.90 (d,J=6.8 Hz, 3H), 0.84 (s, 3H).

1.2.3 化合物6的合成 化合物5 (0.2 g, 0.28 mmol)，咪唑(0.038 g, 0.56 mmol)溶于DMF(4 mL)中，加入TBDPSCl (0.091 mL，0.365 mmol)，室溫反應(yīng)6 h，TLC檢測反應(yīng)完全。蒸出DMF，加入飽和NH4Cl水溶液洗滌，CH2Cl2萃取，合并有機(jī)相。依次用飽和NaHCO3水溶液、蒸餾水、飽和食鹽水洗滌，無水Na2SO4干燥。抽濾、濃縮后硅膠柱柱層析(Petroleum ether: CH2Cl2=1:1-1:1.5→Petroleum ether:AcOEt =20:1)得白色固體6 (0.232 g, 0.25 mmol, 90%)：[α]25D-0.85(c1.2, CHCl3);1H NMR (600 MHz, CDCl3)δ7.69-7.63 (m, 8H), 7.43-7.34 (m, 12H), 5.10 (d,J=5.2 Hz, 1H), 4.95- 4.91 (m, 1H), 3.54-3.48 (m, 2H), 3.44 (dd,J=9.9, 6.1 Hz, 1H), 2.92-2.87 (m, 1H), 2.59-2.52 (m, 1H), 2.39-2.25 (m, 3H), 2.13-2.10 (m, 1H), 1.90 (m, 3H), 1.88-1.82 (m, 3H), 1.71-1.57 (m, 5H), 1.50-1.38 (m, 4H), 1.35-1.26 (m, 1H), 1.22-1,17 (m, 1H), 1.08 (d,J=6.0 Hz, 3H), 1.06 (s, 9H), 1.05 (s, 9H), 0.99 (s, 3H), 0.90 (d,J=5.6 Hz, 3H), 0.83 (m, 3H)；13C NMR (125 MHz, CDCl3)δ213.2, 169.7, 141.2, 135.7, 135.6, 134.8, 134.7, 133.9, 129.5, 129.46, 129.42, 127.6, 127.5, 127.4, 120.80, 75.7, 73.1, 68.7, 55.0, 54.0, 49.8, 43.5, 42.4, 41.8, 39.7, 38.9, 37.1, 36.4, 35.5, 34.8, 31.8, 31.6, 31.2, 27.0, 26.9, 21.1, 20.7, 19.4, 19.3, 19.1, 16.8, 16.7, 13.2; ESI-HRMS calcd for C61H82O5NaSi2[M+Na]+973.5593, Found 973.5576。

1.2.4 化合物7和8的合成 化合物6 (0.3 g, 0.32 mmol)溶于THF(40 mL)中，冰浴下，加入NaBH4(1.8 g, 47 mmol)和CeCl3·7 H2O (3.5 g, 9.6 mmol)，緩慢升至室溫反應(yīng)過夜，TLC檢測反應(yīng)完全。CH2Cl2提取有機(jī)物，濃縮，硅膠柱層析(Petroleum ether:AcOEt=9:1)得到7(22 mg, 0.024 mmol, 18%)和8 (88 mg, 0.096 mmol, 74%)；7:[α]25D-4.7(c0.73, CHCl3);1H NMR (500 MHz, CDCl3)δ5.19 (m, 1H), 5.10 (d,J=5.2 Hz, 1H), 3.56-3.48 (m, 2H), 3.44 (dd,J=9.9, 6.1 Hz, 1H), 3.40 (t,J=6.6 Hz, 1H), 2.41-2.26 (m, 2H), 2.14-2.12 (m, 1H), 1.91 (s, 3H), 1.06 (s, 9H), 1.04 (s, 9H), 0.99 (s, 3H), 0.91 (d,J=6.8 Hz, 1H), 0.89 (d,J=7.1 Hz, 1H), 0.86 (s, 3H);13C NMR (125 MHz, CDCl3)δ170.4, 143.1, 141.3, 135.8, 135.7, 135.60, 135,58, 134.74, 133.9, 130.9, 129.5, 129.44, 129.43, 129.41, 128.8, 127.6, 127.44, 127.42, 120.8, 75.3, 73.2, 72.9, 68.6, 65.6, 55.6, 54.6, 49.9, 42.4, 42.3, 39.6, 37.1, 36.4, 35.8, 35.4, 35.1, 34.0, 31.8, 31.6, 31.4, 29.7, 29.4, 27.0, 26.9, 21.3, 20.7, 19.4, 19.3, 19.1, 16.9, 12.9, 12.5; 8:[α]25D-1.03 (c1, CHCl3);1H NMR (600 MHz, CDCl3)δ7.69-7.63 (m, 8H), 7.43-7.34 (m, 12H), 5.10 (d,J=2.7 Hz, 1H), 5.03-4.98(m, 1H), 3.57-3.40 (m, 4H), 2.36-2.29 (m, 2H), 2.16-2.11 (m, 2H), 2.02 (s, 3H), 1.06 (s, 9H), 1.04 (s, 9H), 0.99 (s, 3H), 0.94 (d,J=5.8 Hz, 3H), 0.91 (d,J=5.6 Hz, 3H), 0.87 (s, 3H);13C NMR (125 MHz, CDCl3)δ170.6, 141.3, 135.77, 135.76, 135.61, 135.59, 134.80, 134.75, 134.0, 129.5, 129.46, 129.42, 127.6, 127.5, 127.4, 120.8, 74.9, 73.1, 69.0, 56.1, 54.5, 49.9, 43.4, 42.8, 42.4, 39.6, 37.1, 36.7, 36.5, 35.8, 35.2, 31.8, 31.6, 31.4, 30.6, 28.0, 27.0, 26.9, 21.3, 20.7, 19.4, 19.3, 19.1, 17.0, 12.5, 12.1; ESI-HRMS calcd for C61H84O5NaSi2[M+Na]+975.5749, Found 975.5745。

1.2.5 化合物9的合成 化合物 7 (23 mg, 0.024 mmol) 溶于吡啶(1 mL)中，加入Ac2O (0.071 mL, 0.75 mmol)，室溫反應(yīng)過夜,TLC顯示反應(yīng)完全。蒸出吡啶，CH2Cl2稀釋，依次用1M HCl、蒸餾水、飽和食鹽水洗滌，無水Na2SO4干燥。抽濾、濃縮，硅膠柱層析(Petroleum ether :AcOEt=20:1)得化合物9 (22 mg, 0.022 mmol, 92%):[α]25D-1.15 (c0.8, CHCl3);1H NMR (500 MHz, CDCl3)δ7.69-7.62 (m, 8H), 7.43-7.34 (m, 12H), 5.18- 5.15 (m, 1H), 5.10 (d,J=5.1 Hz, 1H), 4.81 (t,J=6.5 Hz, 1H), 3.56-3.50 (m, 1H), 3.46-3.42 (m, 2H), 2.45-2.35 (m, 1H), 2.32 (t,J=11.8 Hz, 1H), 2.14-2.08 (m, 2H), 2.00 (s, 3H), 1.93 (s, 3H), 1.06 (s, 9H), 1.04 (s, 9H), 0.98 (s, 3H), 0.97 (d,J=8.6 Hz, 3H), 0.89 (d,J=6.7 Hz, 3H), 0.84 (s, 3H);13C NMR (125 MHz, CDCl3)δ170.8, 170.0, 141.2, 135.7, 135.6, 134.8, 134.7, 133.90, 133.87, 129.5, 129.45, 129.40, 127.6, 127.45, 127.41, 120.84, 75.8, 75.6, 73.1, 68.6, 55.9, 54.4, 49.9, 42.4, 42.3, 39.6, 37.1, 36.4, 35.7, 35.2, 33.2, 31.8, 31.5, 31.4, 29.9, 29.7, 29.4, 27.0, 26.8, 21.3, 21.1, 20.7, 19.4, 19.3, 19.1, 16.7, 12.4, 12.2; ESI-HRMS calcd for C63H86O6NaSi2[M + Na]+1017.5855, Found 1017.5838。

化合物8 (178 mg, 0.19 mmol)溶于CH2Cl2(6 mL)中，加入DMAP (0.046 g, 0.37 mmol)、DIPEA (0.099 mL, 0.57 mmol)和4? MS (600 mg)，室溫下攪拌1 h, 移入-10 ℃下繼續(xù)攪拌30 min，加入MsCl (0.029 mL, 0.37 mmol)，繼續(xù)反應(yīng)，TLC檢測反應(yīng)完全。過濾掉分子篩，AcOEt稀釋，加入冰水，分出有機(jī)相。AcOEt萃取，合并有機(jī)相，依次用蒸餾水、飽和食鹽水洗滌，無水Na2SO4干燥。抽濾、濃縮得黃色固體，不經(jīng)純化直接投入下步反應(yīng)。取DBU (0.057 mL, 0.38 mmol)溶于甲苯(6 mL)中，加入AcOH(0.043 mL, 0.76 mmol)，室溫?cái)嚢璺磻?yīng)30min后,加入制備甲磺酸酯，95 ℃反應(yīng)11 h，TLC檢測反應(yīng)完全。反應(yīng)液冷至室溫，依次用2M HCl溶液、10%的K2CO3水溶液、蒸餾水、飽和食鹽水洗滌，無水Na2SO4干燥。抽濾、濃縮，硅膠柱層析(Petroleum ether:AcOEt=65:1-20:1)得到化合物9 (74 mg, 0.072 mmol,39%)。

1.2.6 化合物10的合成 化合物9 (32 mg, 0.032 mmol)溶于MeCN和CH2Cl2(0.5 mL, v:v=3:2)中，加入TfOH-SiO2(12 mg, 0.024 mmol)，50 ℃攪拌反應(yīng)1 h，反應(yīng)完全。過濾掉硅膠，CH2Cl2淋洗硅膠，濃縮，硅膠柱層析(Petroleum ether:AcOEt=1.5:1)得到化合物10 (15 mg, 0.029 mmol, 91%)：[α]25D+4.1 (c1, CHCl3);1H-NMR (500 MHz, CDCl3)δ5.33 (d,J=4.9 Hz, 1H), 5.24-5.20 (m, 1H), 4.83 (t,J=6.9 Hz, 1H), 3.53-3.51 (m, 1H), 3.48-3.39 (m, 2H), 2.46-2.09 (m, 6H), 2.04 (s, 3H), 2.02 (s, 3H), 1.00 (s, 3H), 0.99 (d,J=6.7 Hz, 3H), 0.91 (d,J=6.7 Hz, 3H), 0.87 (s, 3H);13C NMR (125 MHz, CDCl3)δ170.9, 170.1, 140.7, 121.4, 75.8, 75.7, 75.6, 71.7, 56.0, 54.5, 50.0, 42.3, 39.6, 37.2, 36.4, 35.7, 35.1, 33.1, 31.6, 31.5, 31.4, 29.8, 29.7, 29.4, 21.3, 21.1, 20.7, 19.4, 16.5, 12.5, 12.1; ESI-HRMS calcd for C31H54O6N [M+NH4]+536.3946, Found 536.393 8。

1.2.7 化合物11的合成 化合物10 (0.025 g, 0.048 mmol)，糖基供體3 (168 mg, 0.20 mmol)和分子篩AW 300 MS (100 mg)于反應(yīng)管中，加入1,2-二氯乙烷(1.2 mL)，室溫下攪拌1 h，加入(4-MeOPh)3PAuCl(5.7 mg, 0.0096 mmol)和AgB(C6F5)4(15 mg, 0.0192 mmol)，40 ℃下反應(yīng)20 h，TLC檢測反應(yīng)完全。過濾掉分子篩、濃縮，硅膠柱層析(Toluene:Acetone=38:1-Petroleum ether: AcOEt=2.6:1)得到化合物11(0.072 mg, 0.043 mmol, 90%)：[α]25D+19.9 (c0.65, CHCl3);1H NMR (500 MHz, CDCl3)δ8.00 (d,J=7.7 Hz, 4H), 7.94 (t,J=7.8 Hz, 4H), 7.92-7.87 (m, 4H), 7.86-7.79 (m, 4H), 7.57-7.46 (m, 6H), 7.45-7.30 (m, 15H), 7.29 (d,J=7.6 Hz, 3H), 5.94-5.83 (m, 2H), 5.72-5.58 (m, 2H), 5.50 (dd,J=16.8, 7.4 Hz,2H), 5.25-5.09 (m, 2H), 4.94 (d,J=7.9 Hz, 1H), 4.81 (d,J=7.8 Hz, 1H), 4.75 (t,J=6.8 Hz, 1H), 4.61 (td,J=11.7, 2.9 Hz, 2H), 4.58-4.45 (m, 2H), 4.16-4.13 (m, 2H), 3.68 (dd,J=9.3, 5.6 Hz, 1H), 3.61-3.49 (m, 1H), 3.38 (dd,J=9.3, 5.6 Hz, 1H), 2.45-2.29 (m, 1H), 2.20-2.10 (m, 2H),2.06-2.01 (m,1H),1.97(s, 3H),1.95 (s, 3H), 0.90 (d,J=8.6 Hz, 3H), 0.89 (s, 3H), 0.81 (s, 3H), 0.76 (d,J=6.7 Hz, 3H);13C NMR (125 MHz, CDCl3)δ170.9, 170.1, 166.1, 166.1, 165.8, 165.8, 165.2, 165.2, 165.1, 165.0, 140.2, 133.4, 133.2, 133.1, 133.0, 129.8, 129.74, 129.72, 129.70, 129.6, 129.57, 129.4, 129.3, 128.84, 128.79, 128.38, 128.35, 128.31, 128.26, 121.7, 101.3, 100.1, 80.2, 75.7, 75.4, 75.0, 73.0, 72.96, 72.13, 72.1, 72.0, 71.9, 70.0, 69.8, 63.3, 63.2, 55.9, 54.4, 49.9, 42.3, 39.5, 38.7, 37.0, 36.5, 35.1, 33.2, 33.1, 31.5, 31.3, 29.7, 29.5, 22.7, 21.3, 21.0, 20.7, 19.2, 16.6, 12.4, 12.1; ESI-HRMS calcd for C99H102O24Na [M + Na]+1697.6653, Found 1697.6621。1.2.8 11-deoxyheloside A 的合成 化合物11 (36 mg, 0.021 mmol)和NaOH (63 mg, 1.53 mmol)溶于THF和MeOH (7 mL, v:v=1:1)中，50 ℃下反應(yīng)18 h，用Dowex-50(H+)樹脂調(diào)pH至中性。過濾、濃縮，硅膠柱層析[CH2Cl2:MeOH (8% H2O)=1:1]得到11-deoxyheloside A (16 mg, 0.0205 mmol, 97%)：[α]25D-27.9 (c0.55, MeOH) [lit.2-28.1 (c0.23, MeOH) ];1H NMR (600 MHz, Pyridine-d5/D2O～9:1)δ5.37 (d,J=2.4 Hz, 1H), 5.06 (d,J=7.4 Hz, 1H), 4.83-4.80 (m, 2H), 4.55-4.53 (m, 2H), 4.40-4.15 (m, 9H), 4.11-4.00 (m, 4H), 4.00-3.95 (m, 4H), 3.66-3.64 (m, 1H), 2.78-2.76 (m, 1H), 2.54-2.49 (m, 2H), 2.35-2.30 (m, 1H), 2.21-2.18 (m, 1H), 2.15-2.07 (m, 1H), 2.06-1.97 (m, 2H), 1.93-1.85 (m, 1H), 1.85-1.69 (m, 7H), 1.56-1.30 (m, 9H), 1.22 (d,J=6.2 Hz, 3H), 1.12 (s, 3H), 1.02 (d,J=6.3 Hz, 3H), 0.94 (s, 3H), 0.93-0.86 (s, 5H);13C NMR (125 MHz, CD Cl3)δ141.0, 122.0, 104.7, 102.5, 78.4, 78.3, 75.4, 75.2, 75.1, 71.6, 71.5, 62.70, 62.67, 58.0, 54.9, 50.5, 42.6, 40.4, 39.3, 37.5, 37.1, 37.0, 36.0, 34.2, 32.2, 31.9, 31.5, 30.2, 21.1, 19.4, 17.6, 14.9, 13.5; ESI-HRMS calcd for C39H66O14Na [M + Na]+781.4345, Found 781.4334。

圖2 葡萄糖膦酸酯3的合成

(Reagents and conditions: (a) MeONa/MeOH, r.t., 11.5 h, 87%; (b) TBDPSCl, imidazole, DMF, r.t., 6 h, 90%; (c) NaBH4, CeCl3·7 H2O, THF, 0 ℃-r.t., overnight, 92% (7:8=1:4); (d) Ac2O, Pyridine, r.t., overnight, 92%; (e) MsCl, DMAP, DIPEA, DCM, MS 4?, -10 ℃, 4 h; (f) DBU-AcOH, toluene, 95 ℃, 11 h, 39% for two steps; (g) TfOH-SiO2(500 mg/ mmol), MeCN/ DCM, 50 ℃, 1 h, 91%; (h) 3, (4-MeOPh)3PAuCl, AgB(C6F5)4, AW 300 MS, 1,2-DCE, 40 ℃, 20 h, 90%; (i) NaOH, THF-MeOH, 50 ℃, 18 h, 97%.)

圖3 11-deoxyheloside A的合成
Fig.3 Synthesis of 11-deoxyheloside A

2 結(jié)果與討論

在相轉(zhuǎn)移催化劑作用下，羧酸和酚與溴苷順利反應(yīng)形成糖苷鍵[4]。相轉(zhuǎn)移催化反應(yīng)可以應(yīng)用于葡萄糖膦酸酯供體3的制備。以甲基三辛基氯化銨為相轉(zhuǎn)移催化劑，CHCl3和H2O為溶劑(體積比為1:1)，葡萄糖溴苷1[5]與膦酸單乙酯2[6]進(jìn)行SN2反應(yīng)得到葡萄糖膦酸酯供體3(見圖2)，產(chǎn)率69%。

苷元部分的合成見圖3，化合物4[7]在MeONa/MeOH溶液中選擇性脫除26位的乙酰基，得到化合物5。在咪唑的作用下，化合物5與TBDPSCl反應(yīng)，得到苷元3和26位TBDPS基保護(hù)的化合物6，產(chǎn)率為90%?；衔?經(jīng)Luche還原反應(yīng)得到兩個(gè)非對映異構(gòu)體7和8 (92%, 7:8=1:4)[8]?；衔?的22位羥基為S構(gòu)型，是期望的還原產(chǎn)物?；衔?發(fā)生乙?；磻?yīng)得到化合物9，產(chǎn)率為92%。在DIPEA的作用下，化合物8的22R-OH與MsCl反應(yīng)生成甲基磺酸酯中間體。該中間體在DBU的作用下與AcO-進(jìn)行SN2反應(yīng)得到化合物9[9]，兩步反應(yīng)的產(chǎn)率為39%。四丁基氟化銨(TBAF)溶液脫除化合物9上的TBDPS基得到化合物10[10]，產(chǎn)率為79%。但是生成少量22位乙?；摮母碑a(chǎn)物，分析是體系中堿性過強(qiáng)導(dǎo)致堿性敏感基團(tuán)酯鍵的斷裂。加入等當(dāng)量的醋酸中和體系中的堿性[11]，產(chǎn)率沒有提高。氫氟酸-吡啶溶液脫除化合物9上的TBDPS基時(shí)，產(chǎn)物復(fù)雜[12]。最終用三氟甲磺酸負(fù)載硅膠(TfOH-SiO2)成功脫除9上的TBDPS基團(tuán)得到化合物10[13]，產(chǎn)率提高至91%。

3 結(jié)語

本文以膽甾烷化合物4和葡萄糖溴苷1為原料，通過金催化的鄰炔基膦酸酯的糖苷化反應(yīng)，首次完成了膽甾烷型皂苷11-deoxyheloside A的合成，為合成黃地百合中系列膽甾烷型皂苷奠定了基礎(chǔ)。

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責(zé)任編輯 徐 環(huán)

Synthesis of 11-deoxyheloside A

ZHANG Xue-Wei, WANG Peng, SONG Ni, ZHANG Xiu-Li, WANG Cong, LI Ming

(The Key Laboratory of Marine Durgs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003，China)

Synthesis of 11-deoxyheloside A, a natural cholestan saponin, was accomplished for the first time. Glucopyranosyl phosphonate 3 was prepared in 69% yield by treatment of glucopyranosyl bromide 1 with phosphonic acid monoethyl ester 2 under the phase-transfer catalysis conditions. Cholestan 4 was subjected to Luche reduction followed by acetylation and deprotection oftert-butyldiphenylsilyl mediated by triflic acid supported on silica gel to afford aglycone 10. Glycosylation of 10 with glucopyranosyl phosphonate 3 under the promotion of gold(I) catalyst followed by removal of benzoyl protecting groups in the presence of NaOH in MeOH produced 11-deoxyheloside A in 97% yield.

11-deoxyheloside A； glucopyranosyl phosphonate； gold-catalyzed glycosylation

國家自然科學(xué)基金面上項(xiàng)目(21272220)資助

2014-03-11；

2014-05-16

張雪薇(1987-)，女，碩士生。E-mail:zhangxuewei1314@126.com

** 通訊作者： E-mail:lmsnouc@ouc.edu.cn

R914.5

A

1672-5174(2015)04-072-06

10.16441/j.cnki.hdxb.20140076